Prevalence of pulmonary hypertension in systemic sclerosis and it s correlation with clinical variables

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1 IOSR Journal of Dental and Medical Sciences (IOSR-JDMS) e-issn: , p-issn: Volume 16, Issue 9 Ver. X (September. 2017), PP Prevalence of pulmonary hypertension in systemic sclerosis and it s correlation with clinical variables DR. Bhuban Majhi 1, * DR. Nandita Pal 2 1 Assistant Professor, Department of Cardiology, ICVS, IPGME&R, Kolkata-20 2 Assistant Professor, Department of Microbiology, College of Medicine & Sagore Dutta Hospital, Kamarhati, Kolkata-58 Corresponding author: *DR. Nandita Pal Abstract Introduction: Development of pulmonary artery hypertension (PAH) worsens prognosis of systemic sclerosis (SSc) and can be either isolated precapillary PAH or secondary to interstitial lung disease (ILD). Early diagnosis is of crucial importance. There is scarcity of data on PAH in patients with SSc in India. Objectives: To determine the prevalence and clinical correlates of PAH in systemic sclerosis using noninvasive cardiopulmonary evaluation and in selected cases by cardiac catheterization. Materials And Methods: Clinical and functional characteristics of 100 patients of systemic sclerosis were studied and they were evaluated by echocardiography to detect pulmonary artery hypertension. Our objective was to study the prevalence and the clinical correlation of PAH in SSc Results: PAH was found in 29% patients on echocardiography. Prevalence tend to increase with age of onset and duration of disease. However, it did not differ significantly between patients with limited cutaneous SSc (lcssc) and patients with diffuse cutaneous SSc (dcssc). On binary logistic regression analysis, none of the studied variables had any independent influence on development of PAH. Conclusion: PAH in SSc occurs in a remarkable proportion (29%) of patients without any ominous signs in early stages. Non-invasive screening of patients with SSc for PAH will help in early diagnosis and appropriate timely therapeutic intervention before significant end-organ damage occurs. Keywords: Interstitial lung disease, pulmonary artery hypertension, Raynaud s phenomenon, systemic sclerosis Date of Submission: Date of acceptance: I. Introduction Scleroderma or systemic sclerosis is a generalized connective tissue disorder characterized by microvascular obliteration & increased deposition of collagen, resulting in widespread fibrotic lesions. 1,2 SSc involves not only the skin but a host of other organ systems. Cardio Pulmonary involvement is a common feature of systemic sclerosis and one of the principle causes of death in such patients. 3 Cardiovascular disease in patients with SSc may be due to either primary involvement of the heart by sclerosing disease or a secondary involvement from disease of the kidney or lungs. Cardiac involvement is a poor prognostic factor & PAH itself is a sole ominous prognostic sign in SSc. Various risk factors like increasing age, male gender, digital pits, infarcts and black race have been implicated in the development of pulmonary arterial hypertension in scleroderma. 4 Therefore, resort to all available diagnostic procedures is recommended to achieve an early diagnosis II. Materials And Methods The concerned non randomized crosssectional observational study (without any control) was conducted from January 2010 to June 2012 on 100 patients, presenting with clinical & laboratory evidences of SSc at departments of Rheumatology, General Medicine and Cardiology, at an apex institute in Kolkata, India after prior ethical clearance. Inclusion criteria were based on presence of symmetric sclerosis according to American College of Rheumatology (ACR) criteria. 5 Informed consent was taken from all study subjects. Pregnant females and patients with acute left ventricular failure, valvular heart disease involving mitral valve, atrial fibrillation, chronic liver disease with portal hypertension with porto-pulmonary shunt were carefully excluded from the study. Subjects were clinically evaluated for involvement of musculoskeletal and other organ systems in a case record format. Immunologic markers studied included: ANA (anti nuclear antibody), ENA (extractable DOI: / Page

2 nuclear antibody) Panels. Chest X-ray PA view & 12 lead ECG and HRCT-thorax in selected cases. Echocardiography (2D, M-Mode and color Doppler) were evaluated in all the cases. Confirmation of PAH in borderline cases was done by right heart catheterization & showing a mean pulmonary artery pressure >25 mm of Hg during rest &>30 mm Hg during exercise. Methods of estimating pulmonary artery pressure were based on American Society of Echocardiography guidelines. Estimated pulmonary artery systolic pressure more than 40 mmhg by echocardiography, or, peak tricuspid regurgitation (TR) gradient more than 35mmHg, or, estimated mean pulmonary artery pressure (MPAP) more than 25 mmhg was defined as pulmonary arterial hypertension. Pulmonary artery pressure was compared among different demographic variables and correlations with clinical parameters were studied. Compared disease sub-groups were: DcSSc, LcSSc, CREST syndrome and overlap syndrome. Statistical analysis was done using SPSS16 software. Chi-square test and Fischer s exact test was used for dependent categorical variables. For dependent interval and normal variables between multiple independent groups ANOVA test was used to find out level of significance. Correlation coefficient was calculated for interval and normal variables to find out degree of correlation. Binary logistic regression analysis was done to find out any independent predictors of PAH. III. Results 100 patients were studied, which included 92 females & 8 males (Table 1). Most (74%) of the patients belonged to the age group of Among 100 patients 66 had a rural background and 34 patients belonged to urban area. There was no statistically significant difference of locality among the different disease groups (P>0.5). 66 patients came from lower socioeconomic strata, 34 were from middle income group and none belonged to the higher socioeconomic strata. Among the 100 patients of SSc, 78 had DcSSc and 18 had LcSSc including CREST variant and rest of the 4 patients had overlap syndrome. Mean duration of disease in the total population was 4.84 ± 2.55 years. There was no statistically significant difference of mean duration of disease between different disease groups (P =0.68). Maximum duration of disease was 16 years and minimum duration of disease was 6 months. The most common skin finding was hyperpigmentation which was strikingly high (95%) with predominant diffuse (69%), followed by mottled type (29%). Calcinosis, telengiectasia and digital ulcer was found in 50%, 46% and 48% cases respectively. All of them were found significantly higher in the LcSSc, CREST and overlap syndrome compared to DcSSc group (P<.01). 31% of the patient having digital ulcers developed PAH. Table- 1: Demographic profile and clinical features of study population Variables Our data Mean age of disease presentation 34.99yrs % of females 92(92%) Reynaud s Phenomenon 92(92%) Hyperpigmentation 95(95%) Skin thickening 100(100%) Digital pits/ulcers 48(48%) ANA 90(90%) Dyspnea 42(42%) PAH 29(29%) ILD 37(37%) # Mean PASP 33.5± 11.01mmHg $ Mean MPAP ± 7.21mm Hg # mean pulmonary artery systolic pressure, $population mean of mean pulmonary artery pressure 10 patients had borderline pulmonary artery pressure in echocardiography. They underwent right heart catheterization after proper consent. MPAP more than 25 mmhg at resting condition was confirmed in 5 of these patients. In the other five patients PAH was excluded. Mean pulmonary pressure in the patients who underwent right heart catheterization was mmhg. There was a weak correlation (ρ = ) between between sex of patients and PHTN. It was not statistically significant (P = 0.225). No significant correlation was found between age of patients, duration of disease in years, skin score, duration of Raynaud s phenomenon in months and mean as well as systolic pulmonary arterial pressure. On binary logistic regression analysis none of the variables like age of the patient, duration of disease in years, duration of Raynaud s in months, disease subtype, skin score, presence of calcinosis, or telangiectasia were found to have any independent predictive effect for the development of PAH. However significant correlation was found between right ventricular internal diameter in diastole and pulmonary artery systolic pressure (ρ = 0.23, P =.036). Significant negative correlation was also found between ejection fraction and right ventricular diastolic dimension (ρ = and P =.002).Systolic and mean pulmonary artery pressure in different patient groups has been shown in Table2. DOI: / Page

3 Table-2: Systolic and mean pulmonary artery pressure in different patient groups. (mmhg) Groups SSc DcSSc LcSSc CREST Overlap Male Female MPAP Mean 20.54± 20.09± 22.87± 20.68± 22.30± 23.46± 20.19± St.DEV SPAP Mean 33.46± 33.13± 38.38± ± 32.48± 38.92± 32.99± St.DEV Figure 1: Grading of PAH in SSc patients PAH was detected in 29 patients. Among them, 24 patients had mild PAH (MPAP mmhg) while 4 patients had moderate PAH (MPAP 35-50mmHg) and one patient had severe PAH (MPAP >50mmHg) [Figure 1]. Age wise presentation of PAH has been shown in Figure 2. Figure 2: Bar diagram showing Age wise presentation of PAH in the study population There was increased incidence of PAH among 60-69yr age group compared to other groups, but overall it didn t reach statistical significance (P=0.49). However, year age group had significantly higher DOI: / Page

4 mean pulmonary artery pressure compared to 10-19,20-29,30-39, age groups (P< 0.01) and year age group (P< 0.05). About 27.2% of females and 50% of males had pulmonary artery hypertension. There was no significant difference between the two groups in the incidence of PAH, (P = 0.225). Percentage of PAH in different disease groups were: SSc (29%), DcSSc (29.5%), LcSSc (26.7%), CREST (33.3%), Overlap syndrome (25%). ANA staining pattern and their relationship with presence of PAH is shown in Table3. It was statistically significant (P = 0.048). Table-3: ANA pattern and pulmonary hypertension cross-tabulation ANA patterns PAH Absent (no. of patients) PAH Present (no. of patients) Total Absent Speckle Nucleolar Mixed Homogenous Total The most common pattern observed was speckled (56%), followed by nucleolar (25%) and mixed (speckled/nucleolar, homogenous/nucleolar) (9%). Correlation between disease type and presence of types of ENA was good. AntiScl-70 was found mainly in the diffuse cutaneous scleroderma group whereas LcSSc&CREST group had mainly anti-centromere antibodies. Anti U1rnp was found significantly more in the overlap syndrome patients (P<.0001).Relationship of ENA (extractable nuclear antibody) with presence of PAH is shown in Table-4. Table-4: ENA pattern and pulmonary hypertension cross-tabulation ENA PAH Absent PAH Present Total (no. of patients) (no. of patients) No ENA Anti Scl-70 ab Anticentromere ab AntiU1RNP ab Total However, PAH was not influenced significantly by the presence or absence of ENA or by the type of ENA (P = 0.372). ILD was present in 37 patients. Relationship of ILD & PAH is shown in Table 5. Status of ILD Table- 5: Presence of ILD & PAH cross-tabulation PAH Absent PAH Present (no. of patients) (no. of patients) DOI: / Page Total ILD absent ILD present Total ILD was present in 37 patients (37%) out of 100 patients studied. Those without ILD, 21cases (33.3%) had pulmonary arterial hypertension. 8(21.6%) patients with ILD also had pulmonary artery hypertension. This difference was not statistically significant between the two groups (P = 0.3). IV. Discussion Our study population had more diffuse cutaneous (78%) and less of limited cutaneous scleroderma (18%) variant compared to previous studies both in India and Western world. 6 Mean age of presentation of 34.99± years was similar to other Indian studies and lower than the Western literature. 6,7 There was female preponderance in our study (92/8) similar to other Western studies Maione S et al. 8 Mean duration of disease (4.84±2.55years) was much less in our study compared to previous studies by Mukherjee et al, Meune et al, and Maione S et al but nearly similar to other studies. 7,8,9,10 Most common non respiratory symptom, was Raynaud s phenomenon present in 92% of cases similar to the western literature and most of the Indian

5 literature except for one South Indian study where it was reported to be Skin pigmentation in our study population was similar to one study from India and another from Iraq % of cases of the patient having digital ulcers developed PAH similar to other studies. 13 ANA was found positive in 90% of patients almost similar in frequency between the different disease subsets. This result is at par with the results found in previous studies in India but higher than Western studies. 14,15 Higher incidence of nucleolar pattern than our study was observed by another Indian study. 7 Pulmonary artery hypertension (PASP 40mmHg or MPAP 25mmHg) was found in 29 % of cases. Estimates of the prevalence of scleroderma-associated PAH vary widely in the past literature depending on the definition of PAH used and the diagnostic tools used to identify PAH. Using echocardiography as a diagnostic tool, up to 60% of scleroderma patients have been reported to have PAH. However, using cardiac catheterization as a diagnostic tool to confirm the presence of PAH, a much lower prevalence rate in the range of 8%-12% has been reported. Lower prevalence of PAH was partly due to higher cut off value in our study. However, when 30 mmhg was taken as cut off value the prevalence increased to 56%. Mean pulmonary artery systolic pressure in our study population was33.52± The cut off value of 35mm Hg for trans tricuspid pressure gradient which we used has sensitivity of 75%, specificity of 66% and positive and negative predictive value of 85% and 50% respectively. 16 Our study more or less confirms the finding of Kumar U et al. 17 In our study, prevalence of PAH didn t differ significantly between those with clinically detectable ILD (37 patients) and without ILD. This suggests poor sensitivity of clinical examination in ILD. Probability of subclinical ILD in the rest of the patients probably has accounted for this result. Incidence of ILD was slightly lower in our study patients compared to other studies probably because HRCT thorax couldn t be done in all cases. However, the finding was similar to that of Gaude G S et al. 18 Strengths of our study were: (1) relatively good sample size, (2) heterogeneity of population, (3) detailed echocardiography examination, (4) Tissue Doppler examination in all cases. However, limitations of the study were: i) relatively smaller number of LcSSc cases, ii) not confirming PAH in all cases by right heart catheterization, iii) not determining severity of DLPD by HRCT fibrosis score or doing DLCO, (iv) lack of prospective follow up of echocardiographic data. V. Conclusion Systemic sclerosis involves a multitude of organs with a plethora of complications. Development of pulmonary hypertension is of immense prognostic consequence. However, at the early stages overt clinical features may be absent. Hence early detection of complications is an utmost necessity to relieve patient s sufferings. Noninvasive assessment of PAH in SSc patients enable us to institute early therapeutic intervention to prevent clinical deterioration. Prospective follow up of such patients may confer better understanding of the influence of clinical and demographic variables over the course of disease, behavior of pulmonary artery hypertension over time and its clinical outcome. Better understanding of this dreaded disease and its ominous consequences might assist in the research and development of newer therapies to reduce patient sufferings and to increase their longevity. VI. Bibliography [1]. Rodnan GP, Lipinski E, Lucksick J. Skin thickness & collagen content in progressive systemic sclerosis & localized scleroderma. Arthritis Rheum. 1979;22(2): [2]. LeRoy EC. A brief overview of pathogenesis of scleroderma. Ann Rheum Dis. 1992;51 : [3]. Fauci Al. Harrisons Principle of Internal Medicine. 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